The immune system is normally prevented from mounting an attack against itself, since self is the tissue the immune system is designed to protect. To prevent such attacks, self-reactive lymphocytes are kept in check by potent regulatory mechanisms. Many, but not all, self-reactive T cells are eliminated by negative selection in the thymus. The process of negative selection is not fully understood, but T cells with too high an affinity for self peptides in the context of MHC antigens are eliminated. Paradoxically, those T cells surviving the ordeal of negative selection must then be "positively selected" or expanded. This expansion requires that the T cells be capable of recognizing self peptides in the MHC complex to a certain extent (probably lower affinity) than that seen with negative selection. This process then results in an immune system with a seemingly endless array of specificities.
In North America, five percent of adults, more than two-thirds of them women, suffer from autoimmune diseases (including: multiple sclerosis, rheumatoid arthritis, juvenile diabetes, systemic lupus erythematosus, and thyroiditis). Self-reactive T cells that escape thymic selection are found in all healthy individuals. Therefore, regulation of self reactivity is also maintained, in part, through mechanisms acting outside the thymus. These mechanisms include: active suppression by other cells (i.e., suppressor T cells) that keep these autoreactive lymphocytes under control and by clonal unresponsiveness (anergy), where the cells reactive to self are "anergized." Anergy is thought to involve the inappropriate presentation of the antigenic peptide to the T cell, which leads to unresponsiveness or tolerance. Peptide affinity may play a role in whether the T cell is turned on or off. If the immune system does react against self tissue, a harmful if not potentially fatal autoimmunity develops. One popular theory for autoimmunity is that those people who are genetically predisposed to autoimmune diseases come in contact with infectious agents, such as viruses or bacteria. In the process of controlling the infection, the immune system targets an antigen on the pathogen that resembles a self antigen. These cells then begin to attack self tissue, resulting in autoimmunity.
Insulin-dependent diabetes (IDDM) is one of the most serious and common metabolic disorders. IDDM was once viewed as a rapidly developing illness similar to that which might occur as the result of an acute viral infection, but in fact it results from a chronic autoimmune process that usually exists for years in a preclinical phase. Indeed, the classic manifestations of IDDM--hyperglycemia and ketosis--occur late in the course of the disease after most of the beta cells have been destroyed.
The most striking histological feature of the pancreas of a patient with long-standing IDDM is the near total lack of insulin-secreting beta cells. By contrast, islet cells secreting glucagon (alpha cells), somatostatin (delta cells), or pancreatic polypeptide (pancreatic-polypeptide cells) are preserved. Since beta cells constitute the majority (70 percent) of cells within normal islets, the islets of a patient with long-standing diabetes are abnormally small. Aside from mild interstitial fibrosis and exocrine atrophy, there are no other obvious histologic abnormalities.
At the time of the onset of IDDM or shortly thereafter, most islets are deficient in beta cells, just like the islets in patients with long-standing disease. The remaining islets contain cells with enlarged nuclei, variable numbers of degranulated beta cells, and a chronic inflammatory infiltrate commonly referred to as insulitis. This inflammatory infiltrate consists mostly of CD8 cells plus variable numbers of CD4 cells, B lymphocytes, macrophages, and natural killer cells. The expression of HLA class I molecules on islet cells is increased, whereas class II molecules may be overexpressed on beta cells, macrophages, or endothelium. The expression of intercellular adhesion molecule 1 on the vascular endothelium of the islets is also increased, a feature favoring the adhesion and accumulation of endothelial cells.
The distribution of islets with insulitis in the pancreas of patients with newly diagnosed IDDM can be strikingly uneven. The islets in one pancreatic lobule may appear normal, while those in adjacent lobules may be small or have profound insulitis. This variability may reflect the different insulin-secreting activities of the islet cells, with the most metabolically active beta cells being preferentially destroyed. Histologic studies suggest that an 80 percent reduction in the volume of beta cells is required to induce symptomatic IDDM. Histologic evidence of islet regeneration is uncommon, but it is found in the pancreas of some young patients with IDDM.
The diabetes results from the autoimmune destruction of the insulin-producing .beta. cells of the pancreas and the subsequent metabolic derangements. Although insulin therapy allows most patients to lead active lives, this replacement is imperfect since it does not restore normal metabolic homeostasis. Metabolic abnormalities are thought to be important in the subsequent development of common complications, which include retinopathy, cataract formation, nephropathy, and heart disease.
While the initiating agent of IDDM autoimmunity is not known, it ultimately provokes a loss of immunological tolerance to self-antigens present in insulin-secreting B cells within the pancreatic islets. IDDM begins with an asymptomatic stage, characterized by a chronic inflammatory infiltrate of the islets mediated by white blood cells, including T lymphocytes, B lymphocytes and macrophages which selectively destroys the beta islet cells.
Autoimmunity to beta cells can be initiated by one of two processes. An immune response against a viral protein that shares an amino acid sequence with a beta-cell protein could result in the appearance of antiviral cytotoxic CD8 lymphocytes that react with self-protein on the beta cells. Alternatively, an environmental insult (infection with a beta-cell-tropic virus or expression of a beta-cell superantigen) may generate cytokines and other inflammatory mediators that induce the expression of adhesion molecules in the vascular endothelium of the pancreatic islets. The activation of endothelial cells would allow increased adhesion and extravasation of circulating leukocytes and the presentation of beta-cell antigens from the damaged beta cells by infiltrating macrophages to lymphocytes.
With either alternative, the autoimmune process would be enhanced as soon as lymphocytes reacting with antigens released from damaged beta cells were recruited to the site of inflammation. Genetic susceptibility to IDDM includes an inherent defect in the establishment of peripheral tolerance to beta-cell autoantigens. The continued release of inflammatory cytokines from the inflamed islets could result in the overexpression of HLA class I molecules on beta cells, further potentiating their destruction. As the autoimmune process proceeds, various effector mechanisms of immunologic destruction result in the elimination of beta cells.
The steps in T cell activation in autoimmune diseases are no different than in normal immune regulation. The first step in activation (signal 1) requires interaction among the components of the ternary complex: the T cell receptor, MHC gene products, and the nominal peptide antigen. The second step (signal 2) is not yet clear, but may involve either cytokines or accessory molecules on the antigen presenting cells' surface (such as CD28 ligand). If the T cell receives only signal 1 unresponsiveness or anergy results. Knowing how T cells responds to antigens could allow modulation of the response so that the immune system would respond better to the peptide. Conversely, altering the recognition of a self-peptide could be a useful therapy in managing autoimmune diseases.